Post-translational modification of proteins through acetylation and deacetylation of lysine residues plays a critical role in regulating a variety of cellular functions, including the control of cell shape, differentiation and proliferation. Histone deacetylases (HDACs) are zinc-binding hydrolases that catalyze the deacetylation of lysine residues on histones as well as non-histone proteins. In particular, HDAC6, a class IIb HDAC, is unique amongst the zinc dependent HDACs in humans. Located in the cytoplasm, HDAC6 has two catalytic domains and an ubiquitin binding domain in its C terminal region. The substrates of HDAC 6 include tubulin, peroxiredoxin, cortactin and heat shock protein 90 (hsp90), but not histones. HDAC6 has been identified as necessary for aggresome formation and for survival of cells following ubiquitinated misfolded protein stress.
There is a need for compounds and methods of using these compounds to treat disorders related to HDAC6 function, including cancers, neurodegenerative disorders, peripheral neuropathies, or polycystic diseases.